It is known that compositions comprising the tunica submucosa delaminated from both the tunica muscularis and at least the luminal portion of the tunica mucosa of the intestine of warm-blooded vertebrates can be used as tissue graft materials. See, for example, U.S. Pat. Nos. 4,902,508 and 5,281,422. The compositions described in those patents are characterized by excellent mechanical properties, including high compliance, a high burst pressure point, and an effective porosity index which allows such compositions to be used beneficially for vascular graft constructs and in connective tissue replacement applications. When used in such applications the submucosal graft constructs appear to serve as a matrix for the regrowth of the tissues replaced by the graft constructs. Significantly, too, in over 600 cross-species implants, submucosa-derived graft compositions have never been shown to elucidate a tissue graft rejection reaction.
Submucosa-derived matrices for use in accordance with the present invention are collagen based biodegradable matrices comprising highly conserved collagens, glycoproteins, proteoglycans, and glycosaminoglycans in their natural configuration and natural concentration. One extracellular collagenous matrix for use in this invention is submucosal tissue of a warm-blooded vertebrate. Submucosal tissue can be obtained from various sources, for example, intestinal tissue harvested from animals raised for meat production, including, pigs, cattle and sheep or other warm-blooded vertebrates. Vertebrate submucosal tissue is a plentiful by-product of commercial meat production operations and is thus a low cost tissue graft material.
One limitation of the submucosal graft constructs described in the above mentioned patents is that the size of the graft is restricted by the size of the source material from which the submucosal tissue is prepared. For example, the size of a submucosal tissue graft prepared from intestinal tissues is limited by the length and circumference of the source segments intestinal tissue. Yet several applications of submucosal tissue graft constructs, including hernia repair, skin graft, meningeal coverings, repair of gastroschisis (congenital stomach defects) and organ tissue replacement, often require larger sheets of graft material than can be prepared directly from natural sources.
Large sheets of submucosal tissue can be prepared from smaller segments of submucosal tissue through conventional techniques such as weaving, knitting or the use of adhesives. However, commercial implementation of such techniques are often impractical and expensive. Additionally the use of adhesives or chemical pretreatment to promote adhesion of the tissue strips can compromise the biotropic properties of the submucosal grafts. Thus there is a need for an inexpensive, easily manufactured, large area submucosal tissue graft construct that retains its biotropic properties.
In accordance with one embodiment of the present application large area submucosal tissue graft constructs are formed from multiple pieces of vertebrate submucosa-derived matrices. Unitary sheets (i.e., single piece graft constructs) of submucosal tissue are prepared in accordance with the present invention by fusing multiple strips of submucosal tissue to each other to form a sheet of tissue having a surface area larger than any one of the component strips of submucosal tissue. The present process comprises the steps of overlapping at least a portion of one strip of submucosal tissue with at least a portion of another strip of submucosal tissue and applying pressure at least to said overlapped portions under conditions allowing dehydration of the submucosal tissue. Under these conditions the overlapped portions will become "fused" to form a unitary large sheet of tissue. The large area graft constructs formed in accordance with the present invention consist essentially of submucosal tissue, free of potentially compromising adhesives and chemical pretreatments, and have a greater surface area and greater mechanical strength than the individual strips used to form the graft construct.
Individual strips of submucosal tissue as prepared from the tissues of a warm-blooded vertebrate have mechanical properties that are directionally specific (i.e. physical properties vary along different axes of the tissue). These directional characteristics are governed primarily by collagen orientation within the tissue. The collagen fibers are the load bearing constituents within intestinal submucosal tissue and are predominantly orientated parallel to the axis of the intestine lumen. This longitudinal disbursement of collagen in intestinal submucosal tissue contributes to the directional variability in physical properties of the submucosal tissue constructs.
In accordance with one embodiment of the present invention a unitary pseudoisotropic multi-laminate graft construct is prepared from multiple strips of submucosal tissue. The term "pseudoisotropic" as used herein describes a graft material having approximately similar physical properties along each axis of the graft material. The pseudoisotropic multi-laminate graft constructs of the present invention are prepared from individual strips of submucosal tissue or sheets of submucosal tissue comprising strips of submucosal tissue. The method of preparing the pseudoisotropic graft constructs comprises overlapping a portion of a first strip (or sheet) with a second strip (or sheet), wherein the second strip (or sheet) is orientated in a plane parallel to the first strip (or sheet) but rotated so that the longitudinal axis of the first strip (or sheet) forms an angle relative to longitudinal axis of the second strip (or sheet). Additional strips (or sheets) can be added in a similar manner to create a multi-laminate structure having a desired number of laminate layers. The individual submucosal strips (or sheets) are then fused to one another to form a unitary multi-laminate pseudoisotropic construct by applying pressure at least to the overlapped portions of submucosal tissue .